Current Atherosclerosis Reports (2021) 23:37

https://doi.org/10.1007/s11883-021-00935-2

CORONARY HEART DISEASE (S. VIRANI AND S. NADERI, SECTION EDITORS)

COVID and Cardiovascular Disease: What We Know in 2021

Michael Chilazi 1 & Eamon Y. Duffy 1 & Aarti Thakkar 1 & Erin D. Michos 1,2,3,4

Accepted: 29 April 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review Coronavirus disease 2019 (COVID-19) has been the cause of significant global morbidity and mortality.
Here, we review the literature to date of the short-term and long-term consequences of Severe Acute Respiratory Syndrome
Coronavirus-2 (SARS-CoV-2) infection on the heart.
Recent Findings Early case reports described a spectrum of cardiovascular manifestations of COVID-19, including myocarditis,
stress cardiomyopathy, myocardial infarction, and arrhythmia. However, in most cases, myocardial injury in COVID-19 appears
to be predominantly mediated by the severity of critical illness rather than direct injury to myocardium from viral particles. While
cardiac magnetic resonance imaging remains a powerful tool for diagnosing acute myocarditis, it should be used judiciously in
light of low baseline prevalence of myocarditis. Guiding an athletic patient through return to play (RTP) after COVID-19
infection is a challenging process. More recent data show RTP has been a safe endeavor using a screening protocol. “Long
COVID” or post-acute sequelae of SARS-CoV-2 infection has also been described. The reported symptoms span a large breadth
of cardiopulmonary and neurologic complaints including fatigue, palpitations, chest pain, breathlessness, brain fog, and
dysautonomia including postural tachycardia syndrome (POTS). Management of POTS/dysautonomia primarily centers on
education, exercise, and salt and fluid repletion.
Summary Our understanding of the impact of COVID-19 on the cardiovascular system is constantly evolving. As we enter a new
age of survivorship, additional research is needed to catalogue the burden of persistent cardiopulmonary symptoms. Research is
also needed to learn how acute management may alter the likelihood and prevalence of this chronic syndrome.

Keywords COVID-19 . Cardiovascular disease . SARS-CoV2 . Return to play . Long COVID

Introduction
This article is part of the Topical Collection on Coronary Heart Disease

In the year 2020, the Coronavirus disease 2019 (COVID-19)

* Erin D. Michos
edonnell@jhmi.edu was the third leading cause of death with an estimated 345,323
deaths in the USA [1]. Perhaps more than any other commu-
Michael Chilazi
nicable disease, COVID-19 has captivated the cardiology
mchilazi@jhmi.edu
community due to its apparent links with cardiovascular dis-
Eamon Y. Duffy ease (CVD) [2•, 3–5]. The novelty of the virus led to early
eduffy4@jhmi.edu
reliance on small case reports and theoretical explanations to
Aarti Thakkar explain and predict the impact on CVD. Now, more than a
athakka2@jhmi.edu year since the pandemic’s onset, more mature studies have
1 emerged that refine our understanding of the interplay be-
Department of Medicine, Johns Hopkins University School of
Medicine, Baltimore, MD, USA tween COVID-19 and the heart.
2 Early in the pandemic, patients with cardiovascular comor-
Johns Hopkins Ciccarone Center for the Prevention of
Cardiovascular Disease, Johns Hopkins University School of bidities proved most vulnerable to severe infection [3, 6]. The
Medicine, Baltimore, MD, USA specificity of Severe Acute Respiratory Syndrome
3
Welch Center for Prevention, Epidemiology and Clinical Research, Coronavirus 2 (SARS-CoV-2) for the angiotensin-
Johns Hopkins University, Baltimore, MD, USA converting enzyme-2 (ACE-2) protein fueled further concerns
4
Division of Cardiology, Johns Hopkins Hospital, 600 N. Wolfe about injury to the cardiovascular system [3, 7] and triggered
Street, Blalock 524-B, Baltimore, MD 21287, USA fears about concurrent use of drugs including angiotensin-
 37 Page 2 of 12
converting enzyme inhibitors and angiotensin receptor
blockers [8•]. Early case reports described a spectrum of car-
diovascular manifestations of COVID-19 infection, including
myocarditis, stress cardiomyopathy, myocardial infarction
(MI), and arrhythmia [9–12]. In combating a novel disease,
the cardiology community deployed its most advanced tech-
nology including cardiac magnetic resonance imaging (CMR)
which has characterized acute and chronic consequences of
SARS-CoV-2 infection [13, 14], but often the findings have
left clinicians with more questions than answers.
Now more than a year since the first reported cases in 2020,
the global community finds itself at a critical point in the
timeline of the pandemic. With survivors outnumbering those
infected and with vaccines in distribution, further attention can
be paid to the long-term cardiovascular effects of COVID-19.
Nonetheless, as surges continue across the world owing to
new variants and a lag in vaccine distribution, the medical
community must remain apprised of the latest evidence-
based management of acute COVID-19 infection.
Our understanding of the impact of COVID-19 on the car-
diovascular system is constantly evolving. The rapid pace of
the pandemic and the body of research it has spawned requires
clinicians to adapt management in real time. Herein, we re-
view the latest literature through April 1, 2021 to refine our
current understanding of the acute and long-term conse-
quences of COVID-19 infection on the cardiovascular system.
In acute infection, we revisit our current understanding of
mechanisms of myocardial injury in COVID-19 infection,
the prognostic implications of troponin elevation, and indica-
tions for CMR in diagnosis and management. In resolved
infection, we review considerations for special populations
such as athletes regarding safe return to play, as well as those
with lingering cardiopulmonary symptoms colloquially
known as “long COVID.” We conclude by proposing future
areas of investigation for the interaction between COVID-19
and CVD.
Part I: Acute Infection
Mechanisms of Cardiac Injury in COVID-19
Cardiac troponin is a highly specific test for myocardial inju-
ry, which can be measured by conventional or high-sensitivity
assays. Notably, an elevated troponin (defined as being above
the 99th percentile of upper reference limit) does not neces-
sarily equate to an MI. According to the 4th universal defini-
tion, the criteria for an MI requires a rise/fall pattern of tropo-
nin with at least one value above the 99th percentile along
with other symptoms or signs of ischemia [15]. A type 1 MI
occurs from an acute plaque rupture/erosion event, which has
also been seen in the setting of other viral infections [4, 16],
whereas a type 2 MI is from “demand ischemia” in the context
Curr Atheroscler Rep (2021) 23:37
of an oxygen demand/supply mismatch stemming from
stressors such as hypoxia, hypoperfusion, and tachycardia,
which can occur in COVID-19, as well as other critical ill-
nesses. Both types of MIs have been reported in COVID-19
[2•]. However, paradoxically, there was an approximate 20%
reduction in ST-elevation myocardial infarction (STEMI) rates
during the COVID-19 pandemic. Alternate mechanisms behind
this STEMI reduction have been postulated, but the leading
concern was that patients were avoiding hospital care for fear
of contracting the virus. Beyond acute MI, troponin elevation
can accompany a number of other COVID-19 cardiovascular
presentations including viral myocarditis, indirect cardiac injury
from cytokine storm, stress cardiomyopathy, heart failure (HF),
pulmonary embolism, and arrhythmias, or reflect pre-existing
CVD or cardiac structural abnormalities [17•, 18].
The prevalence of cardiac injury, as measured by an ele-
vated cardiac troponin, on the order of 20–40% among the
first reported patients with severe (hospitalized) COVID-19
attracted the attention of the cardiology and medical commu-
nity at large [6, 17•, 18–23, 24•, 25]. As the virology of
SARS-CoV-2 was further elucidated, its interaction with the
ACE2 protein found on cardiomyocytes supported the physi-
ologic plausibility of direct cardiac viral injury [7]. A prece-
dent had been established by a related coronavirus, SARS-
CoV-1, causing the first SARS outbreak in Asia, whereby
viral RNA in cardiac tissue had been isolated [26].
Furthermore, individuals with CVD, such coronary artery dis-
ease (CAD) and HF [27, 28], and those with CVD risk factors
including hypertension, diabetes, and obesity [27, 29–31]
proved more susceptible to severe infection, heightening con-
cerns that the heart may be a direct viral target and rendered
more vulnerable if compromised.
With respect to the etiology of myocardial injury in
COVID-19, our understanding has evolved since the onset
of the outbreak. Larger histopathologic studies have chal-
lenged early frameworks of cardiac injury, demonstrating
the prevalence of myocarditis and direct viral toxicity to
myocytes to be exceedingly rare [32••, 33]. In one of the
largest cardiac autopsy series to date, Lindner and colleagues
demonstrated that while viral RNA was isolated in cardiac
tissue, in situ hybridization localized the site of infection not
to cardiomyocytes, but rather the interstitium and infiltrating
macrophages [32••]. Additionally, there were zero confirmed
cases of myocarditis by the Dallas criteria. Other pathologic
studies have also failed to document direct cardiomyocyte
infection [33, 34].
Notably, as features of the novel coronavirus were rapidly
catalogued early in the pandemic, little was done to compare
against appropriate control groups. Recent research has situ-
ated COVID-19 in the context of the broader critical care
landscape. Metkus and colleagues compared troponin eleva-
tion in COVID-19 acute respiratory distress syndrome
(ARDS) versus non-COVID-19 ARDS among nearly 250
Curr Atheroscler Rep (2021) 23:37
intubated patients across a large hospital system and demon-
strated that myocardial injury was actually less common in
COVID-19 than non-COVID-19 ARDS, after accounting for
the degree of critical illness and organ dysfunction [35••].
Patients with COVID-19 had worse oxygenation and hemo-
dynamics, reinforcing indirect cardiac injury secondary to crit-
ical illness as the more likely mechanism at play [36]. These
findings are further reinforced by high rates of myocardial
injury seen in other systemic infections beyond COVID-19,
including sepsis, documented in the critical care literature
[37–39].
While other cardiac manifestations including myocarditis,
stress cardiomyopathy, and MI have been described in
COVID-19 and should not be discounted [2, 9–12], situating
COVID-19 in the context of other critical illness has
recalibrated our understanding of myocardial injury to recog-
nize more prevalent mechanisms such as hypoxemia and he-
modynamic compromise (Fig. 1).
Although myocardial injury in COVID-19 may not be
unique to the virus, the degree of critical illness that it can
cause speaks to unique pathogenic attributes. The responsible
mechanism is likely related to its ability to stimulate a robust
inflammatory response. In studies of myocardial injury in
COVID-19, predictors of troponin elevation consistently dem-
onstrated associations with inflammatory markers, including
C-reactive protein (CRP), D-dimer, ferritin, and fibrinogen
[19, 35••, 40]. Pathology studies have supported this
Fig. 1 Symbolic pie chart
illustrating common causes of
indirect myocardial injury and
more rare causes of direct
myocardial injury in COVID-19
infection
Page 3 of 12 37
relationship by demonstrating greater expression of cytokines
with higher viral loads [32••]. While the hyper-inflammatory
phase inflicts much of the respiratory and circulatory compro-
mise mediating indirect myocardial injury in severe infection,
inflammation is previously known to directly mediate CVD,
as seen in atherosclerosis and other hyper-inflammatory states
including sepsis and hemophagocytic lymphohistiocytosis
(HLH) [41]. Cardiomyocytes express receptors to cytokines
including tumor necrosis factor and interleukin-6, the effects
of which can reduce inotropy secondary to alterations in cat-
echolamine signaling and cause cytotoxic injury [42].
Moreover, cytokines alter the vascular endothelium to pro-
mote inflammatory migration and can cause endothelitis,
microthrombi, and microvascular injury which have been de-
scribed in COVID-19 [34].
Echocardiography has further refined our understanding of
myocardial damage in COVID-19, detailing certain functional
patterns of injury [14]. Szekely and colleagues found right
ventricular (RV) dysfunction to be the most common echocar-
diographic abnormality in a series of 100 hospitalized
COVID-19 patients, among nearly 40%, with RV deteriora-
tion most associated with clinical decompensations [43]. RV
dysfunction was also the most common abnormality seen in a
multi-center international cohort of over 300 hospitalized pa-
tients with COVID-19, around 26% [44]. A full spectrum of
dysfunction was seen in both studies, however, including
global and regional left ventricular (LV) systolic dysfunction,
 37 Page 4 of 12
diastolic dysfunction, and pericardial effusions. The preva-
lence of RV dysfunction speaks to COVID-19 being a pre-
dominantly respiratory pathogen with a tendency for deep
venous thrombosis and pulmonary embolism, all of which
can compromise pulmonary vascular resistance and increase
RV loading conditions. Use of speckle-tracking echocardiog-
raphy found reduced basal longitudinal strain to be present in
52% of patients in one single-center study; patients who were
obese, Black patients, or patients with hypertension and dia-
betes were more likely to present with this functional pattern
[45]. Future studies are needed to determine whether these
functional changes are unique to COVID-19 or also seen in
other forms of ARDS and critical illness.
Troponin Elevation: Prognostic Implications
Mechanism of injury aside, detectable troponin elevation
carries prognostic value in acute COVID-19 infection. Shi
and colleagues were among the first to report higher mortality
in those with troponin elevation from a single-center cohort in
Wuhan, finding a threefold to fourfold risk of death [19].
Later, Lombardi and colleagues validated these findings in a
multi-center cohort in Italy with over 600 patients, albeit with
a more attenuated hazard ratio of 1.7 [25]. In one of the most
diverse cohorts studied with over 2000 patients admitted to a
New York City hospital system, Smilowitz and colleagues
illustrated that the risk of death was twofold higher among
patients with troponin elevation [46]. Importantly, the degree
of troponin elevation was associated with more severe critical
illness (defined as ICU admission, need for mechanical ven-
tilation, discharge to hospice, or death). While these seminal
studies defined troponin elevation as greater than the 99th
percentile of the upper limit of normal, Qin and colleagues
illustrated that troponin elevation in COVID-19 infection
was associated with mortality even at thresholds 19–50% low-
er than those traditionally used in clinical settings [47].
Moreover, risk for mortality and adverse outcomes appears
continuous with the degree of troponin elevation; higher tro-
ponin continues to amplify risk, providing clinicians with a
quantitative not just qualitative risk assessment for patients
[24•]. As such, measuring troponin for hospitalized COVID-
19 patients has been integrated into routine clinical practice
and management algorithms. For hospitals, it serves to fore-
cast trajectory and identify patients that may require more
intensive resources particularly in times of scarcity [48].
Several society guidelines including the World Health
Organization and the Chinese Clinical Guidance for
COVID-19 recommend measuring troponin for all admitted
patients, while others including the American College of
Cardiology (ACC) recommend testing when clinically indi-
cated [22].
The association between troponin elevation and mortality
spurred debate whether myocardial injury is a mediator or a
Curr Atheroscler Rep (2021) 23:37
marker of adverse outcomes. In their comparison between
COVID and non-COVID ARDS, Metkus and colleagues
demonstrated that troponin elevation was no longer associated
with mortality after controlling for age, sex, and, importantly,
multiorgan system dysfunction [35••]. Moreover, Giustino
and colleagues have suggested that the presence of troponin
elevation alone may not be sensitive enough to detect clinical-
ly meaningful myocardial injury [44]. In a retrospective,
multi-center international study of echocardiographic findings
in over 300 hospitalized patients with COVID-19, only those
with troponin elevation and echocardiographic abnormalities,
not troponin elevation alone, had significantly higher risk of
in-hospital mortality [44]. These findings suggest that myo-
cardial injury evidenced by detectable troponin, akin to other
markers including lactate, creatinine, and bilirubin, is often the
consequence, rather than the cause of, critical illness and re-
flects the frailty of the underlying substrate.
Role of Cardiac Magnetic Resonance Imaging
The pathophysiologic plausibility of COVID-19 causing di-
rect myocardial infection and early case reports invoking
myocarditis led to increased interest in use of CMR, now the
preferred non-invasive diagnostic modality for acute myocar-
ditis [49]. The first case reports of myocarditis in acute
COVID-19 infection reported prevalence of about 7% [50,
51]; however, these studies were flawed by inconsistent diag-
nostic criteria and limited sample sizes. As discussed previ-
ously in the context of histopathologic studies, the prevalence
of myocarditis in COVID-19 is now appreciated to be ex-
tremely rare, and larger retrospective multi-center cohort stud-
ies have found it to be 1% or less [52]. Recognizing the low
pre-test probability of COVID-19 myocarditis and consider-
ing more likely causes of myocardial injury inform the appro-
priate use of CMR. In particular with CMR, the lengthier
examination time and logistics required to accommodate
exams in intubated patients (including transitioning patients
to and from scanner-safe ventilators) increase exposure risk
for healthcare workers [53].
Subsequently, society guidelines for appropriate use of
CMR during COVID-19 infection have emphasized the con-
sideration of alternative diagnoses and recommended use only
when findings will alter management. The Society of
Cardiovascular Magnetic Resonance (SCMR) endorses the
use of CMR in COVID-19 infection when results have imme-
diate procedural implications, including but not limited to re-
vascularization, valvular interventions, necessary ablations,
immunosuppression, or concern for malignancy requiring car-
diothoracic surgery [54]. When new LV dysfunction or clin-
ical symptoms (e.g., chest pain, arrhythmia) raise concern for
myocarditis, an expert panel from the ACC recommends
CMR only after CAD has been ruled out by angiography or
less invasive modalities such as coronary computed
Curr Atheroscler Rep (2021) 23:37
tomography angiography (CCTA), because the pre-test prob-
ability of ischemia is much more likely than acute myocarditis
[55•]
There may be even greater interest in CMR for the surveil-
lance of survivors following acute infection. Huang and col-
leagues were the first to demonstrate myocardial edema and
fibrosis, evidenced by abnormal T1/T2 signaling and late gad-
olinium enhancement (LGE), respectively, in a small sample
of 26 patients who continued to report cardiac symptoms 50
days from symptom onset [56]. Later, in a prospective cohort
study of 100 unselected patients (i.e., did not necessarily pres-
ent with cardiac symptoms), Puntmann and colleagues dem-
onstrated ongoing myocardial inflammation in 60% of pa-
tients at a median follow-up of 71 days [13]. These findings
raised alarm for long-term consequences for the general pop-
ulation (of note, two-thirds of the participants were not hospi-
talized) as well as select individuals, namely athletes, to be
explored in the subsequent section. Importantly, these studies
did not examine clinical outcomes related to these findings
which remains an important area of investigation. Moreover,
additional work is needed to compare myocardial injury fol-
lowing COVID-19 infection with controls beyond healthy in-
dividuals, because similar CMR findings have been described
following other infectious syndromes such as sepsis [57].
Recommendations for CMR in COVID-19 infection are sum-
marized in Fig. 2.
Part II: Resolved Infection
COVID-19 and Return to Play for Athletes
The question of when a competitive athlete can return to play
(RTP) after COVID-19 infection poses an urgent and impor-
tant challenge to the field of cardiology. The urgency is driven
by the fact that athletic organizations, from the professional to
the recreational, were some of the first to return to full speed
during the pandemic. This collective rush to return began with
little data on how to do so safely after an infection. The im-
portance was clear, as myocarditis is a potential sequela of
COVID-19 infection and a cause of death in young athletes
[58]. Exercising with an active myocarditis can lead to in-
creased inflammation and a proarrhythmogenic milieu.
Furthermore, the athletic heart can have abnormalities in size,
function, and response to exercise that make it challenging to
distinguish from the inflamed or injured heart [59]. Intense
exercise can lead to transient elevations in troponins and im-
aging findings suggestive of cardiac fatigue and myocardial
inflammation [60]. With thousands of athletes eager to return
to action, how to do so safely became a central issue in the
field of cardiology throughout the pandemic.
In May of 2020, the ACC’s Sports and Exercise
Cardiology Section issued its first set of RTP
Page 5 of 12 37
recommendations [61]. For those athletes that experienced a
symptomatic infection, they recommended a 2-week rest pe-
riod after symptom resolution, a cardiac evaluation (electro-
cardiogram, echocardiogram, or high-sensitivity troponin),
and additional cardiac imaging with any abnormalities. If
myocarditis was detected, clinicians were referred to existing
American Heart Association (AHA)/ACC myocarditis guide-
lines which recommend abstaining from athletics for 3–6
months [62]. Six months later, the Section updated and ex-
panded these guidelines to include specific recommendations
based on age and detailed troponin and CMR screening rec-
ommendations [63]. An Expert Consensus Statement follow-
ed, both of which recommended against the use of CMR-
based screening of all athletes with prior COVID-19 infection
[64].
The use of CMR in the RTP setting received much atten-
tion. Published in September of 2020, Rajpal and colleagues
performed CMR in 26 competitive athletes and found that 4
(15%) had CMR findings suggestive of myocarditis and 8
additional athletes (30.8%) exhibited LGE without T2 eleva-
tion suggestive of prior myocardial injury [65]. Brito and col-
leagues then published a study of imaging findings (echocar-
diography and CMR) of 54 student athletes who were recov-
ering from COVID-19 infection [66]. They concluded that
more than 1 in 3 previously healthy college athletes recover-
ing from COVID-19 infection showed imaging features of
resolving pericardial inflammation. These studies are limited
in their size and lack of a control group or clinical endpoints,
but they raised the alarm further for RTP safety, particularly at
the collegiate level.
Fortunately, more recent registry data shows the national
RTP has been a safe endeavor. A study of 789 professional
athletes that underwent a RTP cardiac testing protocol after
COVID-19 infection found imaging evidence of inflammato-
ry heart disease in 5 athletes (0.6%) [67••]. The cardiac screen-
ing protocol included troponin, ECG, and transthoracic echo-
cardiogram; CMR or stress echocardiography was pursued
only in athletes with abnormal initial cardiac screening. No
adverse cardiac events occurred in athletes who underwent
cardiac screening and returned to play.
Guiding a patient through the return to athletics after
COVID-19 infection is a challenging process. COVID-19 data
evolves rapidly, sports cardiology is a relatively nascent field,
and the athletic heart is a unique substrate. This combines to
produce more uncertainty than clear answers when ap-
proaching the return to play. However, as time has passed
and more data emerged, that return, when guided by the cur-
rent screening recommendations, can be done safely.
Long COVID
As healthcare workers and researchers are continuing to learn,
triage, and treat the acute cardiovascular risks of COVID-19,
 37 Page 6 of 12
Fig. 2 Review of the role and
indications for cardiac magnetic
resonance (CMR) imaging in
acute and resolved infection, both
in the general population and
more specifically in athletes.
Abbreviations: LV left
ventricular, ACS acute coronary
syndrome, CCTA coronary
computed tomography
angiography, TTE transthoracic
echocardiography, EKG
electrocardiogram
many outpatient providers are being inundated by patients
with persistent symptoms after acute infection, known in pop-
ular media as “long COVID” [68]. With greater recognition of
this ongoing syndrome, researchers have established the fol-
lowing definitions: post-acute COVID syndrome (PACS) for
persistent symptoms after 3 weeks and chronic COVID after
12 weeks [69, 70]. The National Institutes of Health has also
referred to “long COVID” as post-acute sequelae of SARS-
CoV-2 infection (PASC) [71]. The reported symptoms span a
large breadth of cardiopulmonary and neurologic complaints
including fatigue, palpitations, chest pain, breathlessness,
brain fog, and dysautonomia [69, 70, 72–75].
Researchers have been studying the persistent effects of
COVID-19 since the early days of the pandemic. Of a cohort
of 143 discharged patients in Italy from April 2020, 87%
reported ongoing fatigue and dyspnea at 60 days [76].
Halpin and colleagues in the United Kingdom (UK) demon-
strated that patients requiring intensive care unit–level care
were more likely than general ward patients to report persis-
tent symptoms of fatigue (72% verses 60.3%) and breathless-
ness (65.6% vs 42.6%) after discharge [72]. Another larger
cohort in Michigan found that 159 of 488 (33%) patients en-
dorsed ongoing cardiopulmonary symptoms including cough
Curr Atheroscler Rep (2021) 23:37
and dyspnea at 60 days [77•]. This study was limited by a
large number of patients (greater than 50%) being lost to fol-
low-up.
While early studies estimated the prevalence of long
COVID to be between 30 and 80%, they were limited by a
primary focus on hospitalized patients. Within a non-
hospitalized cohort of 272 individuals across the USA, 35%
reported not being at baseline at 14–21 days after COVID-19
diagnosis [73]. New studies are using mobile technology to
allow responders to directly monitor and report their symp-
toms for both acute and long-term tracking of symptoms [78,
79]. While older individuals with multiple comorbidities are at
higher risk of long COVID, approximately 20% of young
individuals, ages 18–34 and without comorbid conditions,
also continued to report ongoing symptoms at 14–21 days
[73].
With regards to specific cardiovascular symptoms, approx-
imately 20% of individuals reported chest pain and 14% re-
ported palpitations at 60 days [76, 80]. Inflammation and in-
creased metabolic and myocardial demand are thought to con-
tribute to persistent cardiovascular symptoms as this has been
seen in other severe coronavirus infections such as SARS [75,
81, 82]. A rising number of patients and case studies are also
Curr Atheroscler Rep (2021) 23:37
noting a relationship between COVID-19 and postural tachy-
cardia syndrome (POTS) [83•]. POTS is characterized by
change in heart rate with positional change, often accompa-
nied by palpitations and decreased exercise tolerance [83•].
POTS has been previously linked to post-viral illness, but
the exact mechanism is unknown [84, 85]. One hypothesis
connecting POTS with COVID-19 builds on its known inter-
action with the ACE2 protein expressed on neurons.
Researchers hypothesize that this can disrupt the normal reg-
ulation of blood pressure mediated by ACE2, leading to hy-
potension and dysautonomia [74, 85]. Management of POTS
and dysautonomia primarily centers on education, exercise,
and salt and fluid repletion. Agents such as midodrine can
improve vascular tone, while beta-blockers and ivabradine
can help manage palpitations [86]. The prevalence, features,
and management principles of long COVID are summarized
in Fig. 3.
With 20–30% of outpatient individuals and up to 80% of
hospitalized patients having persistent symptoms, the onus is
now on providers and researchers to recognize and manage
the persistent burden of COVID-19 infection. Many recover
slowly on their own through anticipatory guidance and light
Fig. 3 Review of the prevalence
of long COVID, definitions and
symptomatic manifestations, and
current principles of management
for potential COVID/postural
orthostatic tachycardia syndrome
overlap
Page 7 of 12 37
exercise. However, the British Thoracic Society has
established guidelines to follow up all patients regardless of
severity at 12 weeks with a chest X-ray and clinical assess-
ment to evaluate any need for further testing [87]. Those with
severe COVID-19 are recommended to follow up earlier at 4–
6 weeks to evaluate need for further testing as well as multi-
disciplinary rehabilitation [75]. Serial electrocardiograms and
echocardiograms can be used to monitor those with persistent
cardiac symptoms, although advanced imaging should be
discussed on a case-by-case basis.
Conclusion
It has been some time since the global medical community has
confronted a novel disease of pandemic proportions. Unraveling
the mysteries of COVID-19 has been an exercise in diligent
science and experimentation. The latest observational, patholog-
ic, imaging, and clinical studies have clarified the short-term and
long-term impacts of COVID-19 on the cardiovascular system
and updated our understanding in a number of ways.
 37 Page 8 of 12
Fig. 4 Suggestions for future areas of investigation in the domains explored in this review. Abbreviations: POTS postural orthostatic tachycardia
syndrome, CMR cardiac magnetic resonance
Myocardial injury in COVID-19 appears to be predominantly
mediated by the severity of critical illness rather than direct injury
to myocardium from viral particles. While myocardial injury is
not unique to COVID-19 and is seen elsewhere in the critical care
literature in sepsis and ARDS, the hyper-inflammatory response
precipitated by COVID-19 is a unique hallmark and may medi-
ate the more severe clinical courses seen as compared with other
viruses. If anything, COVID-19 has reinforced the critical inter-
action between inflammation and CVD and should spur future
work in this field. While myocardial injury in the form of tropo-
nin elevation is prevalent and prognostic in acute COVID-19
infection, recent studies suggest that troponin elevation is a mark-
er of disease severity and the underlying substrate, rather than an
independent mediator of outcomes.
While CMR remains a powerful tool for diagnosing acute
myocarditis, it should be used judiciously in light of the low
baseline prevalence established in studies to date, as well as risk
of exposure to healthcare personnel. Studies are needed to un-
derstand the clinical relevance of persistent inflammatory signals
seen in survivors and how this may compare or contrast with
those recovering from other common viruses or critical illness.
CMR may have a more focused role in providing recommenda-
tions for at-risk populations such as athletes; however, it should
rarely be the first-line modality and imaging findings alone
should not serve as the basis for diagnosing acute myocarditis.
Lastly, as we enter a new age of survivorship, additional
research is needed to catalogue the burden of persistent
Curr Atheroscler Rep (2021) 23:37
cardiopulmonary symptoms which have significant implica-
tions for patient well-being and global economies regarding
ability to return to work. Research is also needed to confirm
whether existing therapies for dysautonomia including POTS
are effective in the long COVID population, and how acute
management may alter the likelihood and prevalence of this
chronic syndrome. Future areas of investigation across the
domains explored in this review are outlined in Fig. 4.
While questions remain and will continue to emerge re-
garding COVID-19 and CVD, the pandemic has proven that
the scientific community is exceptionally committed and ca-
pable of providing these critical answers.
Acknowledgements The figures in this paper were created with
BioRender.com.
Funding Dr Michos is supported by the Amato Fund for Women’s
Cardiovascular Health Research at Johns Hopkins University.
Declarations
Conflict of Interest The authors declare no competing interests.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Curr Atheroscler Rep (2021) 23:37
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